In the last two decades, intensive pharmacological research concerning gamma-aminobutyric acid (GABA), a neurotransmitter in the central nervous system, has taken place.
Compounds which increase GABA activity are useful in the treatment of anxiety, epilepsy and muscular and movement disorders. Furthermore, these compounds can be used as sedatives.
In U.S. Pat. Nos. 4,383,999 and 4,514,414 (Smithkline Beckman Corporation) some derivatives of N-(4-phenylbuten-3-yl)azaheterocyclic carboxylic acids which have, furthermore, inter alia, phenyl, 4-fluorophenyl, cyclohexyl or thienyl in the 4-position, are described. It is stated therein that the compounds are useful as inhibitors of GABA uptake.
According to J. Pharm. Exp. Therap., 228 (1984), 109 et seq., N-(4,4-diphenyl-3 butenyl)nipecotic acid (designated SK&F 89976A). N-(4,4-diphenyl-3-butenyl)guvacine (designated SK&F 100330A), N-(4,4-diphenyl-3-butenyl)-B-homoproline (designated SK&F 100561) and N-(4-phenyl-4-(2-thienyl)-3-butenyl)nipecotic acid (designated SK&F 100604J) are active inhibitors of GABA uptake.
It is further well recognized in the art that B-homo-proline, nipecotic acid and guvacme are biological equivalents, at least as far as their GABA-like effects regards.
See for example Progress in Medicinal Chemistry 21, 67-120 (1985); ed. Ellis West; Elsevier Science Publishers; Molecular and Cellular Biochemistry 31, 105-121 (1980), and J. Pharm. Exp. Therap., 228 (1984), 109 et seq.
U.S. Pat. No. 5,010,090 teaches the use of N-(Butenyl Substituted) Aza-Hetreocyclic Carboxylic Acids as exhibiting GABA uptake inhibitory properties. In particular, N-[4,4Bis(3-methyl-2-thienyl)-3-butenyl]nipecotic acid and salts thereof are effective GABA uptake inhibitory compounds. These compounds have been found to be effective in the treatment of chronic pain.
A study evaluated tiagabine HCl in animal models of neuropathic and nociceptive pain. An Evaluation of the GABA Uptake Blocker Tiagabine in Animal Models of Neuropathic and Nociceptive Pain, A. Giardina et al. The study did not evaluate the effects of tiagabine HCl in treating humans or pain associated with diabetic polyneuropathy and migraine.